Soluble pharmaceutical formulations of n,n-diaminodiphenyl sulfone for optimal use in the treatment of various diseases

ABSTRACT

The present invention aims to demonstrate that a soluble pharmaceutical formulation can be prepared of N,N′-Diamino-diphenyl sulfone which is useful in the development of an ideal drug for use against cerebral infarction, epilepsy, traumatic spinal cord injury, cranio-encephalic trauma, leprosy, Pneumocystis carinii infections and any condition which requires rapid and complete absorption of the compound. As a representative example of this application, the dissolution of N,N′-Diamino-diphenyl sulfone was evaluated as a neuroprotector in a model of acute cerebral infarction in rats. In this study, N,N′-Diamino-diphenyl sulfone showed significant prevention of brain damage, without presenting adverse effects in animals. It is also shown that the soluble pharmaceutical formulations prepared in this manner produce peak blood levels 30 minutes from oral administration and immediately via the intravenous route.

THE FIELD OF THE INVENTION

The present invention is related to the pharmaceutical productionindustry, and more specifically to the industry of manufacturingmedications to various diseases.

BACKGROUND

Chemotherapeutic treatment of leprosy and Pneumocystis cariniiinfections is performed by the administration of pills ofN,N′-diamino-diphenyl sulfone. The pharmaceutical formulation of thesulfone in solution for use as a drug poses technical problems due tothe low solubility of N,N′-diamino-diphenyl sulfone in an aqueousmedium, therefore, in the present invention, new formulations arepresented that allow solubilization of up to 200 mg of sulfone/3 mL,using co-solvents that are compatible with pharmaceutical safe use inhumans.

N,N′-diamino-diphenyl sulfone solutions have been reported using thesurfactant compound Tween-80, in a ratio of 90% [Helton D R, Osborne DW, Pierson S K, Buonarati M H, Bethem R A., Pharmacokinetic profiles inrats after intravenous, oral, or dermal administration of dapsone, DrugMetabolism and Disposition 28: 925-929 (2000)], Drug Metabolism andDisposition 28: 925-929 (2000)], with the serious disadvantage thatTween-80 is a toxic compound at the necessary concentrations to dissolvesulfone, which precludes its use in humans.

The present invention has the purpose of achieving water-solublemixtures of N,N′-diamino-diphenyl sulfone for faster absorption of theactive molecule with the possibility of applying it in unconsciouspeople and that allows its safe use in human beings as a medication fortherapeutic administration in the form of solutions by any systemicroute, including all enteral and parenteral routes.

N,N′-diamino-diphenyl sulfone is a drug currently used in thechemotherapy of leprosy and in the prophylaxis against Pneumocystiscarinii pneumonia. Recently, N,N′-diamino-diphenyl sulfone (dapsone) hasshown other uses as a neuro-protective and anti-epileptic, whichfrequently require administration to unconscious patients, making itimpossible for the administration of solid pharmaceutical formulations.These new applications for dapsone have been patented (patent No. MX246.892, patent No. MX 264.912) and the soluble forms are more suitablefor such applications, because faster drug absorption is required intreatments, compared with the speed of solid formulations.

SUMMARY

The present invention describes a product for therapeutic use based onthe dissolution of N,N′-diamino-diphenyl sulfone in a mixture ofsolvents compatible with its medicinal use in humans. TheN,N′-diamino-diphenyl sulfone is used with new applications thatfrequently require administration to unconscious patients, therefore,the solid formulations of the drug currently in use are unsuitable.

Searching for options to dissolve N,N′-diamino-diphenyl sulfone, it wasfound that mixtures of ethanol/propylene-glycol/glycofurol/benzylalcohol/water with various additives such as thickeners, stabilizersand/or flavorings, allow for obtaining stable products perfectly suitedfor administration by any enteral or parenteral routes. The solutionswere obtained by synthesis of N,N′-diamino-diphenyl sulfone, a compoundwith the following formula:

In all cases, USP-grade solvents and reagents were used, free ofpyrogens.

The dissolution tests were carried out in glass or stainless steelcontainers in volumes of 10 mL to 5 L, placing mixtures of co-solventswith 200 mg of N,N′-diamino-diphenyl sulfone/3 mL. TheN,N′-diamino-diphenyl sulfone dissolution was determined by visualinspection of the containers, after vigorous shaking.

A simplex algorithm was used to determine the optimum ratio of mixturesof ethanol/propylene glycol/glycofurol/benzyl alcohol/water needed todissolve the N,N′-diamino-diphenyl sulfone.

For stability studies of the N,N′-diamino-diphenyl sulfone solution,glass vials were used with 10 ml capacity, sealed with a gas burner.

Sterilization of vials with the soluble formula was performed in anautoclave at 110° C.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 illustrates the graph representing time in days on the x-axis,and the DDS concentration on the y-axis.

FIG. 2 shows a histological section of a rat brain in which cerebralinfarction was produced, and only the drug vehicles were applied.

FIG. 3 shows a histological section of a rat brain in which cerebralinfarction was produced and the solution was applied intravenously.

FIG. 4 shows a histological section of a rat brain in which cerebralinfarction was produced and the oral solution was applied.

FIG. 5 shows the plasma concentration profile when the oral formulationis applied.

FIG. 6 shows the plasma concentration profile when the formulation isapplied intravenously.

DETAILED DESCRIPTION Synthesis of N,N′-diamino-diphenyl sulfone

N,N′-Diamino-diphenyl sulfone can be synthesized in various ways, butthe following synthesis route is offered as an example.

This synthesis was performed in two steps:

1.60 g of acetanilide were poured into an Erlenmeyer flask and heatedslowly with flame until the melting of the solid was complete. Theresulting viscous liquid was cooled in a glass of ice, ensuring that thesolidified material stayed at the bottom of the flask. 165 ml ofchloro-sulfonic acid were added in a single portion, without removalfrom the ice bath. Subsequently, the flask was removed from the ice,mixing carefully, and the reaction was allowed to be take place for 10minutes, at the end of which the reaction mixture was again heated untilthe total solubilization of the remaining acetanilide, allowing it toreact again for 10 more minutes. The product was allowed to cool and wascarefully poured into a container with ice and water, filtering theprecipitate and washing it with cold water. The precipitate wascollected, dissolved in chloroform and extracted three times with water,collecting the chloroform phase, which was placed in an ice bath,precipitating the purified thionyl chloride (Reported melting point ofthe intermediary: 149° C.).

2. 123.6 ml of anhydrous nitrobenzene were poured into a glass reactor,89.2 g of aluminum chloride were added and heated slowly; then, 41.3 gof thionyl chloride was added to the hot mixture, heating the reactionmixture at a temperature of 140-145° C., and 13 g of acetanilide wereslowly added, maintaining the reaction temperature for two hours. At theend of this period, the product of the reaction was poured into 104 mlof water acidified with hydrochloric acid then dark crystals wereprecipitated, and were recrystallized with dilute acetic acid. Thesecrystals were refluxed with 5N hydrochloric acid for 30 minutes, thenneutralizing the reaction mixture, with which white crystals wereprecipitated (raw DDS), which was recrystallized again with ethanol.

Chemical Characterization of the Synthesized Compound.

To determine the authenticity of the synthesized compounds, theirmelting point thereof were obtained, which was from 151 to 153° C. forthe reaction intermediary of thionyl chloride, and from 172 to 175° C.for DDS.

The melting points reported for these compounds are 149° C., 175-176° C.for the intermediary and the DDS, respectively.

PREFERRED MODE OF CARRYING OUT THE INVENTION

The use of ethanol/propylene glycol/glycofurol/benzyl alcohol/water invarying proportions to the solution of N,N′-Diamino-diphenyl sulfone isuseful for preparing a medication against various diseases, such ascerebral infarction, epilepsy, traumatic spinal cord injury,cranio-encephalic injury, cerebral hemorrhage, subarachnoid hemorrhagedue to aneurysm, leprosy, Pneumocystis carinii infections and anycondition that requires a rapid and complete absorption of the compound,administered by any systemic route.

Drug administration can be carried out in dosages of 0.2 mg/Kg to 12mg/Kg and can be repeated as often as necessary for periods from 1 to 7days.

Example 1 Dissolution of N,N′-Diamino-Diphenyl Sulfone forAdministration as a Solution for Administration by any Enteral orParenteral Route

From 50 mg to 500 g of N,N′-diamino-diphenyl sulfone are weighed andplaced in a test tube. 5 volumes of a mixture containing 2.9 volumes ofpropylene glycol, 1.25 volumes of Ethanol and 0.85 volumes of water areadded. They are shaken until achieving the complete dissolution of theN,N′-diamino-diphenyl sulfone.

The solution obtained is transferred to a glass vial which is thensealed and sterilized by autoclave.

To determine whether the dissolution of N,N′-diamino-diphenyl sulfonewas complete and whether the sterilization procedure caused anappreciable degradation of N,N′-diamino-diphenyl sulfone, the solutionsof N,N′-diamino-diphenyl sulfone were analyzed with high-resolutionliquid chromatography with ultraviolet light detection.

Evaluation of the Neuroprotective Effect of Soluble Formulations ofN,N′-Diamino-Diphenyl-Sulfone.

To evaluate the neuroprotective capacity of the soluble formulations ofdapsone, its effect was tested in a model of brain ischemia in rats. Inthis model, there was permanent cerebral ischemia in rats due topermanent occlusion of the middle cerebral artery, as described below:

Selective permanent brain ischemia was produced in animals by theintroduction of an intraluminal suture through the carotid artery. Allanimals received continuous anesthesia during the surgical procedure,with 1.5% Halothane through a face mask. The animals were placed in thesupine position, the anterior cervical region was fixed and shaved inorder to make an incision in the midline of the manubrium sterni to thesternohyoid muscle region and was continued to its lateral edge,identifying in this site the medial border of the sternocleidomastoidand superficial cervical fascia in the deep layer, which was influencedto expose the common carotid below and within the di-gastric belly flow.

A sharp dissection of the common carotid was made to the hypoglossalloop. The carotid bifurcation, the external carotid artery and itsoccipital and thyroid branches were identified, and the latter two weretied with 8-0 monofilament, as well as with electro-coagulation for itsposterior cut. The internal carotid artery was dissected over a lengthof about 5 mm, and at that time, the pterygopalatine artery wasidentified. A microchip was placed in it, or alternatively, it was tiedwith 6-0 monofilament. After removing the flow through these arterialtributaries, 3-0 nylon monofilament was introduced in the directiontowards the internal carotid artery, through the stump of the externalcarotid artery, at a length of 17 mm from the bifurcation. The wound wasclosed and the animal was allowed to recover with food and water ondemand. In all cases, ischemia was confirmed by macroscopic observationand by the position of the thread.

Evaluation of the Neuroprotective Effect of Soluble Formulations ofN,N′-Diamino-Diphenyl-Sulfone in Rats.

Serial histological sections were made from the brains of the rats,performing the stain of hematoxylin and eosin, to determine the area ofinjury. The representative result of this neuroprotective effect, foranimals treated with the new pharmaceutical forms, and the effect of thevehicles, is shown in FIG. 2.

FIG. 2 shows that the area of injury is significantly lower in animalstreated with the new soluble forms of N,N′-Diamino-diphenyl sulfone,compared to control animals treated with the vehicle.

Pharmacokinetic Profile of Soluble Pharmaceutical Formulations ofN,N′-Diamino-Diphenyl Sulfone in Healthy Volunteers.

Soluble forms of N,N′-Diamino-diphenyl sulfone (DDS) were administeredin solution both orally (FIG. 3), as well as intravenously (FIG. 4) in18 healthy human volunteers, and the plasma concentrations ofN,N′-Diamino-diphenyl sulfone were determined at different times. FIGS.3 and 4 show the results of that analysis.

After calculating the area under the curve of the pharmacokineticprofiles for each rat, average bioavailability of more than 92% wasobtained for the oral form, taking the area under the curve of theintravenous route as 100% bioavailability. This result indicates thatthe soluble oral form is absorbed optimally in the digestive tract. Themaximum concentration for the oral form is obtained on average in ahalf-hour, while reports in the literature indicate a time to reachmaximum plasma concentration of 2 to 3 hours for the solid forms (BreenG A, Brocavich J M, Etzel J V, Shah V, Schaefer P, Forlenza S.,Evaluation of effects of altered gastric pH on absorption of dapsone inhealthy volunteers, Antimicrobial Agents and Chemotherapy 1994September; 38(9):2227-2229)

1. The dissolution of N,N′-Diamino-diphenyl sulfone, using mixtures ofa) ethanol/b) propylene glycol/c) glycofurol/d) benzyl alcohol/e) waterin varying proportions to obtain a product for therapeutic purposes, byany route of administration.
 2. The solution of N,N′-Diamino-diphenylsulfone obtained by the dissolution to claim 1 wherein it containsamounts for administering dosages of 0.2 mg/Kg to 12 mg/Kg. 3.N,N′-Diamino-diphenyl sulfone in a mixture of ethanol/water in varyingproportions from 0 to 25% v/v.
 4. N,N′-Diamino-diphenyl sulfone,according to claim 1, wherein the mixture ratio can range from 0 to 95%of solvent, ethanol from 0 to 25%, propylene glycol from 0 to 70%,benzyl alcohol from 0 to 20%, glycofurol from 0 to 25%, water from 5 to90%.
 5. N,N′-Diamino-diphenyl sulfone according to claim 1, wherein themixture can range from: a) Ethanol 0 to 25% b) Propylene glycol 0 to 60%c) Benzyl alcohol from 0 to 20% d) Glycofurol from 0 to 25% e) Waterfrom 5 to 90%.
 6. N,N′-Diamino-diphenyl sulfone according to claim 2,where the preference is: a) Ethanol 25% b) Propylene glycol 58% c)Benzyl Alcohol 1% d) Glycofurol 5% e) Water 11%.
 7. The use ofethanol/propylene glycol/glycofurol/benzyl alcohol/water in varyingproportions according to claim 1, to dissolve N,N′-Diamino-diphenylsulfone, useful for preparing a drug against various diseases such ascerebral infarction, epilepsy, traumatic spinal cord injury,cranio-encephalic trauma, cerebral hemorrhage, leprosy, Pneumocystiscarinii infections and any condition that requires rapid and completeabsorption of the compound, administered by any systemic route.
 8. Theuse of the solution of N,N′-Diamino-diphenyl sulfone, according to claim1, at a dose of 0.2 mg/kg to 12 mg/kg, useful for preparing a medicationagainst cerebral infarction, epilepsy, traumatic spinal cord injury,cranio-encephalic trauma, cerebral hemorrhage, leprosy, Pneumocystiscarinii infections and any condition that requires rapid and completeabsorption of the compound, administered by any systematic route.
 9. Theuse of the solution of N,N′-Diamino-diphenyl sulfone, according to claim1, at doses between 5 and 300 mg per day, useful for preparing amedication against cerebral infarction, epilepsy, traumatic injury tothe spinal cord, cranio-encephalic trauma, cerebral hemorrhage, leprosy,Pneumocystis carinii infections and any condition that requires rapidand complete absorption of the compound, administered by any systemicroute.
 10. The use of the solution of N,N′-Diamino-diphenyl sulfone,according to claim 6, where the preferred administration may be repeatedevery 24 hours.
 11. The use of ethanol/propyleneglycol/glycofurol/benzyl alcohol/water in varying proportions accordingto claim 2, to dissolve N,N-Diamino-diphenyl sulfone, useful forpreparing a drug against various diseases such as cerebral infarction,epilepsy, traumatic spinal cord injury, cranio-encephalic trauma,cerebral hemorrhage, leprosy, Pneumocystis carinii infections and anycondition that requires rapid and complete absorption of the compound,administered by any systemic route.
 12. The use of ethanol/propyleneglycol/glycofurol/benzyl alcohol/water in varying proportions accordingto claim 3, to dissolve N,N′-Diamino-diphenyl sulfone, useful forpreparing a drug against various diseases such as cerebral infarction,epilepsy, traumatic spinal cord injury, cranio-encephalic trauma,cerebral hemorrhage, leprosy, Pneumocystis carinii infections and anycondition that requires rapid and complete absorption of the compound,administered by any systemic route.
 13. The use of ethanol/propyleneglycol/glycofurol/benzyl alcohol/water in varying proportions accordingto claim 4, to dissolve N,N′-Diamino-diphenyl sulfone, useful forpreparing a drug against various diseases such as cerebral infarction,epilepsy, traumatic spinal cord injury, cranio-encephalic trauma,cerebral hemorrhage, leprosy, Pneumocystis carinii infections and anycondition that requires rapid and complete absorption of the compound,administered by any systemic route.
 14. The use of ethanol/propyleneglycol/glycofurol/benzyl alcohol/water in varying proportions accordingto claim 5, to dissolve N,N′-Diamino-diphenyl sulfone, useful forpreparing a drug against various diseases such as cerebral infarction,epilepsy, traumatic spinal cord injury, cranio-encephalic trauma,cerebral hemorrhage, leprosy, Pneumocystis carinii infections and anycondition that requires rapid and complete absorption of the compound,administered by any systemic route.
 15. The use of the solution ofN,N′-Diamino-diphenyl sulfone, according to claim 2, at a dose of 0.2mg/kg to 12 mg/kg, useful for preparing a medication against cerebralinfarction, epilepsy, traumatic spinal cord injury, cranio-encephalictrauma, cerebral hemorrhage, leprosy, Pneumocystis carinii infectionsand any condition that requires rapid and complete absorption of thecompound, administered by any systematic route.
 16. The use of thesolution of N,N-Diamino-diphenyl sulfone, according to claim 3, at adose of 0.2 mg/kg to 12 mg/kg, useful for preparing a medication againstcerebral infarction, epilepsy, traumatic spinal cord injury,cranio-encephalic trauma, cerebral hemorrhage, leprosy, Pneumocystiscarinii infections and any condition that requires rapid and completeabsorption of the compound, administered by any systematic route. 17.The use of the solution of N,N′-Diamino-diphenyl sulfone, according toclaim 4, at a dose of 0.2 mg/kg to 12 mg/kg, useful for preparing amedication against cerebral infarction, epilepsy, traumatic spinal cordinjury, cranio-encephalic trauma, cerebral hemorrhage, leprosy,Pneumocystis carinii infections and any condition that requires rapidand complete absorption of the compound, administered by any systematicroute.
 18. The use of the solution of N,N′-Diamino-diphenyl sulfone,according to claim 5, at a dose of 0.2 mg/kg to 12 mg/kg, useful forpreparing a medication against cerebral infarction, epilepsy, traumaticspinal cord injury, cranio-encephalic trauma, cerebral hemorrhage,leprosy, Pneumocystis carinii infections and any condition that requiresrapid and complete absorption of the compound, administered by anysystematic route.
 19. The use of the solution of N,N′-Diamino-diphenylsulfone, according to claim 2, at doses between 5 and 300 mg per day,useful for preparing a medication against cerebral infarction, epilepsy,traumatic injury to the spinal cord, cranio-encephalic trauma, cerebralhemorrhage, leprosy, Pneumocystis carinii infections and any conditionthat requires rapid and complete absorption of the compound,administered by any systemic route.
 20. The use of the solution ofN,N′-Diamino-diphenyl sulfone, according to claim 3, at doses between 5and 300 mg per day, useful for preparing a medication against cerebralinfarction, epilepsy, traumatic injury to the spinal cord,cranio-encephalic trauma, cerebral hemorrhage, leprosy, Pneumocystiscarinii infections and any condition that requires rapid and completeabsorption of the compound, administered by any systemic route.